Nitric oxide (NO) has been reported to play various roles in the physiological activity in the body of mammal; for example, as a vasodilator in the vascular system [Pharmacol. Rev., vol. 43, 109-142 (1991)], as a factor showing tumor cell eradicating activity in the leukocyte system [Curr. Opin. Immunol., vol. 3, 65-70 (1991)], and as a neurotransmitter in the nervous system [Neuron, vol. 8, 3-11 (1992)]. Basically, NO is produced from L-arginine by NO synthase (NOS), and to date, the presence of three kinds of isoforms of genetically nerve NOS, vascular endothelial NOS and inducible NOS (iNOS) has been clarified [Cell, vol. 70, pp. 705-707 (1992)]. Based on the mode of presence, the former two are also referred to as constitutive NOS (cNOS) as contrasted with the latter as iNOS.
The cNOS is considered to be present in the vascular endothelial cell and neurocyte, be calcium calmodulin-dependant, produce a small amount of NO by activation of various receptor stimulations, and to be responsible for the aforementioned physiological control. In contrast, iNOS is known to be induced by various cytokines, bacterial lipopolysaccharides (LPS) and the like to produce a large amount of NO in a sustained manner in macrophage, neutrophile and the like, and to damage and hurt cells and tissues at a production site, while showing the above-mentioned physiological activity [Immunol. Today, vol. 13, 157-160 (1992)]. Known cells and tissues that express iNOS are the aforementioned cells, as well as hepatocyte, kupffer's cell, glia cell, vascular smooth muscle cell, vascular endothelial cell, inner membrane of cardiac muscle, cardiac muscle cell, mesangial cell, chondrocyte, synovial cell, pancreatic β cell, osteoclast and the like [FASEB J., vol. 6, 3051-3064 (1992), Arch Surg., vol. 128, 396-401 (1993), J. Biol. Chem., vol. 44, 27580-27588 (1994), J. Cell. Biochem., vol. 57, 399-408 (1995)].
Heretofore, L-arginine analogs [Pharmacol. Rev., vol. 43, 109-142 (1991)], aminoguanidine [Br. J. Pharmacol., vol. 110, 963-968 (1993)], S-ethylisothiourea [J. Biol. Chem., vol. 43, 26669-26676 (1994)] and the like have been reported to inhibit iNOS.
It is also known that cytokines, such as TNF-α, IL-1, IL-6 and the like, are secreted by various cells such as monocyte, macrophage, lymphocyte, neutrophile, fibroblast, vascular endothelial cell and the like and widely involved in biological defense and immune system based on inflammation [The Cytokine Handbook, 2nd ed Academic Press Limited (1994), Advances Immunol., vol. 62, 257-304 (1996)].
It has been clarified that TNF-α and IL-1 show activities such as (1) fever, (2) activation and promoted chemotaxis of inflammatory cells such as macrophage, neutrophile and the like, (3) induction of inflammatory cytokines such as IL-1, IL-6, IL-8, TNF, CSF and the like and acute protein, (4) promotion of production of various chemical mediators such as NO, O2−, PAF, prostaglandin, leukotriene, protease and the like; and that IL-6 shows activity such as (1) introduction of acute protein, (2) increasing blood platelet, (3) differentiation and activation of lymphocyte and NK cell, (4) growth of osteoclast, and the like. However, excess production of these cytokines and production thereof at inappropriate sites and time is inconvenient for organisms. For example, these cytokines have been found to be involved in various diseases such as cachexia, allergic disease, rheumatoid arthritis, abscess, graft rejection, anemia, arteriosclerosis, autoimmune disease, diabetes, central nervous system disease, inflammatory bowel disease, cardiac disease, hepatitis, cirrhosis, nephritis, osteoporosis, psoriasis, septic shock and the like, caused by protozoan, bacteria, fungi, virus, cancer and the like. It has been described that a substance that suppresses or antagonizes production of TNF-α, IL-1, IL-6 and the like can be a therapeutic drug of these diseases [Eur. J. Immunol., vol. 18, 951-956 (1991), Immunol., vol. 83, 262-267 (1994), Proc. Natl. Acad. Sci., vol. 93, 3967-3971 (1997), J. Immunol., vol. 147, 1530-1536 (1991), Immunol. Today, vol. 12, 404-410 (1991)].
Because substances that suppress NO production by iNOS inducible cell, thereby to treat cardiac disease, autoimmune disease, inflammatory disease, septic shock and the like are considered to be effective as a prophylactic and therapeutic drug of various diseases, such as arteriosclerosis, myocarditis, cardiac myopathy, brain ischemic disorder, Alzheimer's disease, multiple sclerosis, septic shock, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerular nephritis, osteoporosis, pneumonia, hepatitis, psoriasis, graft rejection, pain and the like, and because the cells targeted by cytokines are diversified over, for example, the inflammation system, the vascular system, the central nervous system, the hematopoietic system, the endocrine system and the like, the biological activities thereof are considered to be diversified, too. These compounds, however, are not entirely satisfactory from the aspect of activity, and are associated with problems that they inhibit not only iNOS but also cNOS responsible for physiological activity, and the like. Therefore, the invention provides an improved agent for the prophylaxis or treatment of diseases such as cardiac disease, autoimmune disease, inflammatory disease, septic shock and the like.